Non-insulin-dependent diabetes mellitus (NIDDM) is charactarized by an impaired insulin response to elevated glucose levels which, in contrast to insulin-dependent diabetes mellitus (IDDM), is not primarily due to loss of beta-cells even though the total beta-cell mass is moderately diminished in NIDDM (1, 2). Despite the apparent multifactorial nature of the pathogenesis of NIDDM, and regardless of whether beta-cell dysfunction is primary of secondary, the most substantial and uniform morphological aspect of this disease with respect to the islets of Langerhans is the deposition of amyloid. These deposits (islet amyloid=IA) which are exclusively limited to the islets of Langerhans occur in more than 90% of NIDDM patients and in over 65% of adult diabetic cats (3-5). IA occurs also in old persons and in aged cats but less frequently and to a lesser extent. In contrast to the NIDDM cases, no IA deposits have been found in association with IDDM.
In significance of IA has been a matter of discussion ever since the first description of the phenomenon in 1900 (6). Although isolated and purfied IA might potentially have served as a useful marker for detection of an islet cell dysfunction associated with the development of NIDDM it has not been possible heretofore to achieve a chemical analysis of IA. The principal obstacle to chemical characteriszation and to amino acid sequencing of the subunits has resided in the difficulty encountered in effectuating solubilization (depolymerization) of the IA fibrils (7). This difficulty of solubilizing IA, which has contributed to the elusive nature of this material, constitutes a direct contrast to the two major systemic forms of amyloid (i.e. AA or secondary amyloid and AL or primary amyloid) both of which can be depolymerized with 6M quanidine hydrochloride after suspension in distilled water. These properties of systemic forms of amyloid have permitted purification and direct chemical analysis of the amyloid fibril protein subunits.
In all instances, amyloid is a pathological deposit of polymerized subunits which form beta-pleated sheet fibrils (8). Many different types of amyloid exist and these may occur systemically or be localized to individual tissues (9). Each type is characterized by its protein subunits, and up to now seven different proteins have been shown to be capable of forming amyloid fibrils in vivo (10-17). Amyloid in polypeptide hormone producing tissues has been proposed to consist of corresponding hormones (18, 19). This is best supported for human medullary carcinoma of the thyroid where the subunits of the amyloid fibrils formed have been shown, after amino acid sequencing, to consist of procalcitonin (13). Since amyloid deposits are common in insulin producing tumors (19) and because there is a close relationship between the amyloid fibrils in islet beta-cells and insulin-producing tumors, it was believed previously that the amyloid in these locations is derived from insulin or its precursor. The invention is based on our discovery that IA mainly contains a hitherto unknown polypeptide, now named IAPP.
In an International Type Search Report compiled by the Swedish Patent Office during the priority year, the references 26-31 have been cited. References 26-28 deals with unsuccessful attempts to isolate and characterize the major component of islet amyloid. Reference 29 describes a systemic form of amyloid that is completely distinct from islet amyloid. See for instance the preceding paragraph. References 30 and 31 have been cited as defining the general state of the art and have not been considered to be of any particular relevance.